High-Throughput Screening to Identify Chemical Cardiotoxic Potential

Cardiovascular (CV) disease is one of the most prevalent public health concerns, and mounting evidence supports the contribution of environmental chemicals to CV disease burden. In this study, we performed cardiotoxicity profiling for the Tox21 chemical library by focusing on high-throughput screening (HTS) assays whose targets are associated with adverse events related to CV failure modes. Our objective was to develop new hypotheses around environmental chemicals of potential interest for adverse CV outcomes using Tox21/ToxCast HTS data. Molecular and cellular events linked to six failure modes of CV toxicity were cross-referenced with 1399 Tox21/ToxCast assays to identify cardio-relevant bioactivity signatures. The resulting 40 targets, measured in 314 assays, were integrated via a ToxPi visualization tool and ranking system to prioritize 1138 chemicals based upon formal integration across multiple domains of information. Filtering was performed based on cytotoxicity and generalized cell stress endpoints to try and isolate chemicals with effects specific to CV biology, and bioactivity- and structure-based clustering identified subgroups of chemicals preferentially affecting targets such as ion channels and vascular tissue biology. Our approach identified drugs with known cardiotoxic effects, such as estrogenic modulators like clomiphene and raloxifene, anti-arrhythmic drugs like amiodarone and haloperidol, and antipsychotic drugs like chlorpromazine. Several classes of environmental chemicals such as organotins, bisphenol-like chemicals, pesticides, and quaternary ammonium compounds demonstrated strong bioactivity against CV targets; these were compared to existing data in the literature (e.g., from cardiomyocytes, animal data, or human epidemiological studies) and prioritized for further testing.